Is APOA5 p.Asp332fs (c.990_993del) pathogenic?

APOA5 p.Asp332fs (c.990993del) is classified Pathogenic/Likely pathogenic in APOA5 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-08-05). Very rare (popmax 0.00223%, eas); Associated with Cardiovascular phenotype.

What condition is associated with APOA5 p.Asp332fs (c.990_993del)?

APOA5 p.Asp332fs (c.990_993del) is associated with Cardiovascular phenotype, hyperlipoproteinemia type V, hypertriglyceridemia 1 (ClinVar).

How common is APOA5 p.Asp332fs (c.990_993del) in the general population?

APOA5 p.Asp332fs (c.990_993del) is very rare (popmax 0.00223%, eas) (gnomAD).

APOA5 p.Asp332fs

c.990_993del · rs774150500 · VCV978324

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.6	GERP 3.3, phastCons 0.99
Overall
CADD	18.42	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,890 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000805% 13/1,614,144 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,890
Admixed American	0.00167%	60,014
South Asian	0.0011%	91,092
European (non-Finnish)	0.000847%	118,006

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: APOA5
Protein: p.Asp332fs
Coding: c.990_993del
MANE Select: NM_001371904
dbSNP: rs774150500
Type: Microsatellite
Location: chr11:116790236 (GRCh38)
Gene constraint: LOEUF 1.146 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.38

Full APOA5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hyperlipoproteinemia type V hypertriglyceridemia 1

Similar variants

APOA5 p.Asp332Glu Uncertain significance ★ ⚠ same residue
APOA5 p.Gln97Ter Pathogenic ★★ same condition
APOA5 c.161+3G>A Uncertain significance ★★ same condition
APOA5 c.161+5G>C Uncertain significance ★★ same condition
APOA5 p.Ala244Ser Uncertain significance ★★ ⚠ same condition
APOA5 p.Ala302Val Uncertain significance ★★ ⚠ same condition
APOA5 p.Ala82Val Uncertain significance ★★ ⚠ same condition
APOA5 p.Arg226Cys Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/apoa5-p-asp332fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown